Molecular Insights into the Incorporation of Platinum-Based Drugs into Lipid Aggregates.

Platinum-based (Pt-based) compounds remain a cornerstone of chemotherapy, yet their clinical use is limited mainly due to poor tumor specificity and systemic toxicities. Fatty acid conjugation has emerged as a promising strategy to overcome the limitations of conventional platinum drugs by enhancing lipophilicity, improving cellular uptake, and potentially acting as prodrugs with altered physicochemical properties and binding kinetics to biomolecular targets. The covalent conjugation of lipophilic fatty acids also improves the compatibility of Pt-based compounds with lipid-based delivery systems, facilitating their incorporation. In this study, we employed atomistic molecular dynamics (MD) simulations to investigate the interactions between a series of Pt-based compounds, including cisplatin and fatty acid-conjugated analogs (CapryP, ArP, SteariP, ElaidP, and OleP), and biologically relevant phospholipids (DOPC, DSPE, and DPPG). Simulations revealed the spontaneous self-assembly of lipid-drug mixtures into micelle-like aggregates, driven by hydrophobic interactions and modulated by the chemical structure of the conjugated moieties. Cluster analysis demonstrated variation in aggregation dynamics among the compounds, with hydrophobic chain length and unsaturation degree influencing the rate and stability of complex formation. These findings provide insights at the molecular-level, shedding light into the molecular attributes that govern the incorporation of fatty acid-Pt-based conjugates into lipid assemblies, highlighting the potential of structural modifications to enhance their delivery within lipid-based systems.